The research field of ferroptosis has seen exponential growth over the past few years,
since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent
phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including
redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids,
lipids and sugars, in addition to various signalling pathways relevant to disease.
Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly,
therapy-resistant cancer cells, particularly those in the mesenchymal state and prone
to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological
modulation of ferroptosis, via both its induction and its inhibition, holds great
potential for the treatment of drug-resistant cancers, ischaemic organ injuries and
other degenerative diseases linked to extensive lipid peroxidation. In this Review,
we provide a critical analysis of the current molecular mechanisms and regulatory
networks of ferroptosis, the potential physiological functions of ferroptosis in tumour
suppression and immune surveillance, and its pathological roles, together with a potential
for therapeutic targeting. Importantly, as in all rapidly evolving research areas,
challenges exist due to misconceptions and inappropriate experimental methods. This
Review also aims to address these issues and to provide practical guidelines for enhancing
reproducibility and reliability in studies of ferroptosis. Finally, we discuss important
concepts and pressing questions that should be the focus of future ferroptosis research.